Tuesday, 31 May 2011

Of the women exposed to natalizumab during pregnancy, 29 women gave birth to 28 healthy children; one child was born with hexadactyly (an extra finger), 5 pregnancies ended in an early miscarriage and one woman decided to undergo an elective termination of pregnancy. Importantly MS activity did not rebound during pregnancy or post partum after natalizumab was withdrawn. These data support the notion that an elective termination of pregnancy due to natalizumab exposure may not be necessary.

"Woman may find these data reassuring. However, I will still advise having a planned pregnancy."

Inflammation detected using brain MRI is the most sensitive marker of disease activity in MS. This study investigated the clinical consequences of MRI activity in 75 PwMS treated with two different first line DMTs. Transient remission of disease occurred in 46% of subjects (partial responders) and only 23% of subjects had complete remission (responders). MRI remission was never achieved in ~30% of subjects (non-responders). The lack of MRI remission during treatment with interferon beta-1b or glatiramer acetate was associated with higher relapse rate and worsening of physical and cognitive function.

" This study illustrates the moderate impact of 1st-line DMTs on disease activity and that only a minority of PwMS completely respond to these treatments. This study suggests that if you choose the maintenance and escalation treatment strategy you can't simply rely on clinical relapses to assess disease activity we need to do MRIs. When last did your consultant perform an MRI to assess whether or not your are responding to your treatment?"

Please remember that all agents are associated with particular side-effects and other attributes; hence the decision on which one is more appropriate for a particular person will require some careful thought. Individualised Medicine!

CoI: I have conflicts of interests in relation to all of these compounds. Barts and The London is involved in the clinical development of all of these compounds and I personally have received compensation for acting as an advisor to Biogen-Idec (BG12), Merck-Serono (Cladribine), Novartis (Fingolimod), Teva (Laquinimod) and Sanofi-Aventis (Teriflunomide).

Sunday, 29 May 2011

I had to give a talk yesterday, at the European Neurological Society (ENS) Meeting in Lisbon, on how to handle the complexity that the emergence of new DMTs are creating. I was trying to make the argument for early aggressive treatment and the expert patient, i.e. to involve the patient as much as possible in the decsion making process so as to ensure long-term adherence to therapy and to manage expectations (what will the impact of the treatment be on my disease and on my life). One point I stressed is that MS causes disability in the majority of people with the disease given sufficient time and that the average life expectancy is reduced by about ~10 years.

In support of this strategy is the recently presented 21-year follow-up of the orginal cohort of patients treated with interferon-beta-1b in the pivotal Betseron/Betaferon study. The follow-up showed that treatment with IFNbeta-1b reduced the risk of death by 47% compared to patients receiving placebo for 3 years and then being offered treatment with IFNbeta-1b; in otherwords a delay in treatment by 3 years signficantly affected your chance of being alive at 21 years. We only need to treat 8 patients with IFNbeta-1b to prevent 1 death due to MS 21 years later. There is one caveat to these data; IFNbeta has many actions in the body and the improvement in survival may be due to other mechanisms independent of MS. For example, IFNbeta may improve survival by preventing cancers or possibly heart disease.The latter could not be answered in this study as there were too few subjects.

Saturday, 28 May 2011

The following is fingolimod's time-line. This is typical example how long it takes to develop a DMT for MS. If the PPMS trial is positive fingolimod will only be available for people with PPMS in late 2014 or early 2015.

Thursday, 26 May 2011

We are desperately trying to employ a very bright young doctor and MS researcher from Iran. This is the response from our HR department:

"Bottom line: there are not many options available, unless the person is an renowned expert in their field and can apply for tier 1. If you want to employ them as a post-doctoral scientist - then QMUL will have to apply via tier 2. Tier 2 (restricted) - there are no institutional quotas but a UK-wide quota of 1500 per month. If the quota has been reached for the month, we can keep re-applying until we get a visa. However to apply, the post must be advertised in the UK and EU for 4 weeks, and evidence is required to demonstrate that no suitable person is available in the of the whole of the UK & EU. If they have funding (from a non-UK source) - they can come for a year as an Academic Visitor for a max of 12 months, BUT AGAIN this is quite difficult and they have to fulfill the following conditions:

(1) be an eminent senior doctor or dentist coming to take part in research, teaching or clinical practice; (2) they must not receive funding for their work from any United Kingdom source; (3) not be filling a normal post or a genuine vacancy; (4) not stay in the UK for more than 12 months; (5) not intend to take employment in the UK; (6) intend to leave the UK at the end of their visit; and (7) be able to maintain themselves and any dependents without having recourse to public funds (or be adequately maintained and accommodated by relatives or friends)."

"I predict in 10 years time the UK will be a scientific also-ran and will be way down the scientific league tables."

As a follow-up to our previous posting on the impact of FTY720 or Fingolimod on brain atrophy. Good news! After several months of logistical issues we finally randomised and dosed our first patients in the FTY720 PPMS trial.

"It is good to be able to finally offer our patients with primary progressive MS the possibility of being enrolled in a clinical trial. For once I don't feel like a therapeutic nihilist when it comes to PPMS."

CoI: Dr Klaus Schmierer is the PI at our site, I have received personal compensation for sitting on a steering committee for the phase 4 development of Fingolimod and we have received grant support for work on our animal model from Novartis who market Fingolimod.

Wednesday, 25 May 2011

In response to one of the comments from my posting in relation to disease outcomes.In MS damage to nerve processes called axons releases proteins into the spinal fluid. One class of these proteins are neurofilaments, which supports the structure of the axon. I think of neurofilaments as the scaffolding or supporting structures of axons. What is important is that if neurofilament levels are raised in the spinal fluid it indicates that axons are being damaged at that point in time and is predictive of a worse prognosis. Effective disease-modifying and neuroprotective therapies should reduce or even normalise the levels of spinal fluid neurofilament levels. This is the basis of our proposal to test neuroprotective therapies. The study design is to take PwMS in the progressive phase of the disease and do a lumbar puncture to measure the level of spinal neurofilament levels. Patients are then randomised to a putative neuroprotective therapy or placebo. After 6 months another lumbar puncture is done and the spinal fluid neurofilament levels measured. If the neuroprotective therapy works it should reduce the level of neurofilament levels in the spinal fluid compared to baseline and this shoudl not occur in PwMS on placebo. This sort of trial means an answer can be done very quickly within 6-12 months on only 30 subjects. At the moment clinical trials in progressive MS involve hundreds of patients and last 3 or more years. What do you think? Would you have two lumbar punctures? I must remind you that we have gotten much better at doing lumbar punctures; we now use atraumatic needles and sonar or x-ray guidance that limit the potential complications.

Sildenafil (aka Viagra), commonly used to treat sexual dysfunction in men with MS, has been reported to be neuroprotective. In this study, the investigators showed that sildenafil reduces the clinical signs of disease in a mouse model of MS.

"I wonder if Pfizer would be interested in taking this forward in humans? I suspect not with Viagra, but may be one of the longer acting compounds in this class of drugs."

Sunday, 22 May 2011

I have just attended an International task force meeting on disability outcomes in MS; the main attendees were clinicians working in MS (trialists), several of the MS Societies (US, UK and Canada), ECTRIMS, industry and more importantly the FDA, EMA and Health Canada (regulatory agencies responsible for licensing drugs). Unfortunately there were no people with MS attending. It was clear that we need to establish better outcome measures to capture MS disability. Several problems were highlighted with the EDSS and MSFC (multiple sclerosis composite), the main outcome measure we use today. The main conclusion of the meeting was that we need to improve what we have, i.e. make the EDSS better and to add components to the MSFC to make it clinically meaningful. At the moment the MSFC measures cognition (PASAT), upper limb function (9-hole peg test) and lower limb function (25-ft timed walk). It is very important that the outcome measures we use and develop have clinically meaningfulness; this is particularly important for the FDA. Patient related outcome measures (PROMS) were relatively short changed in that they are probably the easiest way to get PwMS engaged with monitoring their own disease and are clinically meaningful by design as they get to the core of the issue of disability. I was particularly impressed by the concept of item banking; this is a bank of many questions or mini outcome scales that assess many different functions. PwMS create their own personalised outcome scale from items relevant to their life, for example running, playing the piano, memory, writing, working, etc. This scale is then used longitudinally to track the impact of MS over time. Another idea that was floated was the use of smart phones to collect this data via mini apps. The disappointment for me personally was how little longitudinal data we have on body fluid biomarkers and the reluctance for the group to accept serial lumbar punctures to monitor the disease. How do you feel about having annual lumbar punctures to monitor your disease?

Saturday, 21 May 2011

Following the re-examination of its previous negative opinion, the European Medicines Agency has granted fampridine a conditional marketing authorisation; i.e. it has been licensed in Europe to improve the walking of PwMS who have walking disability.

Friday, 20 May 2011

The following are the results of our survey on CCSVI that has just closed. Surprisingly only 10% of respondents thought that CCSVI is the cause of MS. Almost a quarter of people think it is an established disease. In medicine we define a disease when we can correlate the clinical presentation and course with a specific pathology; the so called clinico-pathological correlate. At the moment we don't have enough information to make this call in relation to CCSVI; CCSVI is therefore is a non-disease at present. The latter situation may change with the emergence of new data.

An assessment of the clinical outcomes and survival in 35 patients with natalizumab-associated PML.
At the time of analysis, 25 patients (71%) had survived. Survivors were younger and had lower pre-PML disability scores and a shorter time from symptom onset to diagnosis (mean 44 vs 63 days) compared to fatal cases. In the non-fatal cases, 86% had unilobar or multilobar disease on brain MRI at diagnosis, whereas 70% of those with fatal cases had widespread disease. Among survivors with at least 6 months follow-up, disability levels were evenly distributed among mild, moderate, and severe, based on clinician-reported scores.

"In summary, it is bad news if you develop PML on Natalizumab. If you are on Natalizumab please urge your neurologist to discuss the risk with you and to send your bloods off to see if you have previously been exposed to the virus. This information will allow you to better define your risk of developing this complication."

COI: I was the Chief Investigator on the Affirm trial in the UK and have received payments as a consultant from Biogen-Idec in relation to Natalizumab and PML.

This study has tried to assess if there are any differences in relation to the onset of MS and disease progression between people with familial and sporadic MS. Results: Disease onset tended to occur slightly earlier (months) and involved more sites at onset (multifocal) in people with familial compared to sporadic MS, i.e. no family history of the disease. Notably, there was a correlation in relation to disease progression within sibling pairs as well as a higher risk for siblings than for controls to become secondary progressive. Conclusions: The authors conclude that familial MS differs from sporadic MS with respect to age at onset, multifocal involvement as first clinical event, and conversion into secondary progression.

Memory impairment is common in PwMS. In this study the investigators examined the effect of L-amphetamine on auditory/verbal and visual/spatial memory. L-amphetamine improved memory (48.5%) more than placebo (1%); importantly this effect was specific to patients with baseline memory impairment.

"L-amphetamine is an old drug and is handicapped by its potential for abuse, its scheduling and it side effect profile; it causes anxiety, loss of appetite, loss of weight and insomnia. Hopefully this study will lead to follow-on studies to confirm the results. Having a drug to help memory will be very helpful."

Monday, 16 May 2011

"I had a query whether or not I prescribe LDN. The simple answer is no, I don't. The evidence that it works in MS is not robust enough and it is not licensed for use in MS. Despite my position I will grant the proponents of its use that there is a scientific rationale why it may work in MS. LDN stimulates a part of the brain called the hypothalamus to secrete a hormone called ACTH. This hormone travels to the adrenal glands and stimulates the gland to produce natural steroids. In addition to this action LDN partially blocks receptors in the brain for the bodies own opiods (endorphins and enkephalins) this in turn may stimulate increased production of these compounds that may have positive symptomatic effects. In addition to benefits, or potential benefits as in the case of LDN, all drugs have risks; thankfully in the case of LDN the risks appear to be minimal, which makes it a relatively safe drug."

Repair of demyelinated axons requires activation of the genetic and cellular programs to promote remyelination in existing or newly recruited oligodendrocyte precursor cells. This is a very complex process. However, a protein Lingo is a natural inhibitor or remyelination and is therefore a therapeutic target in MS. Investigators have shown that anti-LINGO-1 reagents promote remyelination in cell cultures and in animal models of MS. As a result of this work it appears that Biogen-Idec are doing a phase 1 safety study in MS to see if this strategy is safe to take forward.

"The good news is that there are strategies to promote repair that are being tried in MS!"

Saturday, 14 May 2011

Unfortunately there are no DMTs that have been shown to work in PPMS. The reasons for this are complex and related to many factors; (1) firstly our poor understanding of the mechanisms underlying non-relapsing progressive MS; (2) the assumption that PPMS is not that inflammatory (in my opinion an incorrect assumption); (3) poor application of diagnostic criteria for PPMS* and (4) poor trial design (the EDSS is simply not up to the task of measuring disease progression over a short period of time).

he good news is that there are two well-designed PPMS trials recruiting patients at present: the first and most advanced is the Fingolimod (Novartis) study and the Ocrelizumab (anti-CD20, Roche) is about to start. The latter study is based on the observations from a subgroup analysis of the Rituximab PPMS trial that showed younger patients (<51 years) and those with active MRI scans (Gd-enhancing lesions) responded to treatment; i.e. had a slower rate of disease progression. Please see Hawker et al. Ann Neurol. 2009 Oct;66(4):460-71.

* The original McDonald diagnostic criteria required patients to have an abnormal spinal fluid analysis. However the revisions of these criteria have not made this an absolute requirement, which has altered the natural history of PPMS. Patients with normal CSF analysis do better than those with a negative CSF.

There is a high prevalence of depression in PwMS and other neurological disorders. A systematic review and meta-analysis of 20 randomised controlled trials showed that anti-depressant treatment was associated with a greater than two-fold chance of remission (odds ratio = 2.23; 95% confidence interval = 1.54 to 3.23; number needed to treat=7).

"Good news is that anti-depressants work in PwMS; bad news they are not that effective."

Tuesday, 10 May 2011

Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some neurologists interrupt treatment of patients with MS despite a lack of data regarding the safety of treatment interruption. The aim of this study was to determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in RRMS. Findings: a consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease.

"Hopefully, risk stratification as proposed in a previous post will help neurologists make informed decisions and prevent abrupt withdrawal."

COI: I was the Chief Investigator in the UK on the AFFIRM study and have received consulting fees from Biogen-Idec in relation to Natalizumab.

Saturday, 7 May 2011

There is an assumption at this meeting, amongst the key opinion leaders (KOLs) attending, that with the increasing complexity created by the release of the new wave of MS DMTs, patients will not be able to assimilate all the relevant information and be in a position to make treatment decisions for themselves. I disagree! Similarly, the debate yesterday about induction vs. escalation therapy was interesting in that the majority of neurologists favoured escalation therapy over induction therapy as it is supposedly “safer”. I am not sure we have enough long-term data on the new oral agents to make this claim. Interestingly, it was also stated that induction therapies (alemtuzumab, cladribine and anti-CD20) were the only therapies likely to offer the potential of a cure, as they do something fundamental to the immune system. If that is the case why can’t PwMS choose for themselves?

CONCLUSIONS: The combined effect of prior immunosuppressant use and natalizumab treatment duration identifies subpopulations of patients at lower or higher risk of developing PML. Anti-JCV antibody testing is an additional promising risk stratification tool being evaluated in ongoing studies.

"PwMS will find this information helpful in deciding on whether or not to start or stop Natalizumab treatment based on their JCV serostatus, previous treatment history and duration of Natalizumab treatment."

COI: I was the Chief UK Investigator on the AFFIRM study and have received consultancy fees from Biogen-Idec and Elan Pharmaceuticals in relation to the development of Natalizumab

Thursday, 5 May 2011

The latest rendition of the continuously evolving diagnostic criteria for MS. The use of MRI for demonstration of dissemination of MS lesions in space and time has been further simplified; in some circumstances dissemination in space and time can be established by a single scan, which will allow earlier diagnosis in some cases.

"Whether these new criteria will result in earlier access to treatment is unlikely, particularly in the UK."

Tuesday, 3 May 2011

In this study on over 3,600 study participants ~25% of the participants did not take any vD3 supplements, while 47% took up to 2000IU per day, 1.8% took over 10,000IU and the majority took up to 5000IU per day. Despite taking as much as 10,000IU Vitamin D3 per day, no participant in the study demonstrated vD3 levels in the "toxic" range of >200ng/ml. For those severely deficient in vD3, each 1000IU of increased supplementation resulted in an increase of 10ng/ml in vD3 blood levels. Those with existing blood levels above 30ng/ml demonstrated an 8ng/ml increase in blood level for every 1000IU given, and those with existing levels above 50ng/ml showed an increase of only 5ng/ml for every 1000IU of Vitamin D3. This study demonstrates how difficult it would be to take enough vD3 to reach toxic levels. As blood levels increase, absorption decreases.
Perhaps the most surprising finding was the dose of vD3 necessary to ensure that 95.7% of the population achieved levels of >40ng/ml was 9,600IU. Although such doses are an order of magnitude higher than those currently recommended, these calculated daily intakes are of the same magnitude as produced by a single dose of UV-B radiation achieved during a few minutes of solar UVB exposure near noon in midsummer, assuming nearly complete skin exposure.

"These results demonstrate the safety of taking 5,000U or 10,0000U of vD3 per day and the importance of measuring blood levels of vD3 to ensure that the dose taken is adequate to achieve optimal blood levels."

Sunday, 1 May 2011

Rieckmann et al. OBJECTIVE: To investigate the relationship between cladribine tablets-induced changes in lymphocyte counts and therapeutic effect in patients with MS. Lymphocytes are the white blood cells that is thought to cause MS. RESULTS: Changes in the absolute lymphocyte counts from baseline, i.e. before treatment, correlated with MRI activity. CONCLUSIONS: Cladribine-induced changes in lymphocyte counts moderately correlate with MRI and clinical outcomes, and suggest that certain biological markers of cladribine activity are associated with the observed treatment effect.

"These results are from additional analyses done on the CLARITY study and indicate that in the future it may be possible to modify the dose of Cladribine based on its effects on the lymphocyte counts; similar to what happens with other drugs in this category."

Farrell et al. OBJECTIVE: To evaluate the effect of interferon-beta and neutralizing anti-interferon-beta antibodies (NAbs) on markers of EBV infection and activity in subjects with MS. RESULTS: 100% of MS subjects in this study were seropositive for EBV infection, which confirms the published data. 25 % (IFN-beta treated) were NAb positive; in other words their immune systems had rejected IFN-beta by making antibodies against it; these antibodies then prevent IFN-beta from working. Patients who were NAB-negative had lower antibody levels against EBV than subjects who were NAB-positive. CONCLUSIONS: This results suggests that IFN-beta may be working against EBV. We have previously shown that the titre of antibody against EBV correlates with MS disease activity on MRI.

"This study provides indirect evidence that EBV is important in the pathogenesis of MS and that IFN-beta may be working in MS by suppressing EBV. The lattter is not surprising as IFN-beta is a potent anti-viral drug. On an individual level if you have been on IFN-beta for more than 12 months you should have yourself tested for NABs; there is no point in being on a drug that is being prevented from working by NABs."

COI: This study was done by Dr Rachel Farrell in our group.

Acknowledgement: This study was supported by a grant form the MS Society of Great Britain and Northern Ireland.

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Holistic Management of MS ver. 7.0

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General Disclaimer: Please note that the opinions expressed here are those of the individual bloggers and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry, Queen Mary University of London or Barts Health NHS Trust.

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